ClinVar Miner

Submissions for variant NM_000143.3(FH):c.1500G>A (p.Trp500Ter) (rs886039368)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000254913 SCV000321645 pathogenic not provided 2017-12-27 criteria provided, single submitter clinical testing This variant is denoted FH c.1500G>A at the cDNA level and p.Trp500Ter (W500X) at the protein level. The substitution creates a nonsense variant, which changes a Tryptophan to a premature stop codon (TGG>TGA), and is predicted to cause loss of normal protein function through protein truncation. Also published as FH c.1371G>A (p.Trp457X) using alternate nomenclature, this variant has been reported in a large family with HLRCC as well as in an individual with a single cutaneous leiomyoma (Gardie 2011, Buelow 2016). In addition, the adjacent nucleotide change resulting in the same nonsense variant c.1499G>A (p.W500X), reported as p.W458X using alternate nomenclature, was identified in the compound heterozygous state with another FH variant in a child with fumarate hydratase deficiency and significantly decreased FH enzyme activity (Coughlin 1998). Based on currently available evidence, we consider FH c.1500G>A to be pathogenic.
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000445633 SCV000537270 pathogenic Multiple cutaneous leiomyomas 2017-01-17 criteria provided, single submitter clinical testing
Ambry Genetics RCV000494499 SCV000581678 likely pathogenic Hereditary cancer-predisposing syndrome 2016-03-07 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Other data supporting pathogenic classification,Rarity in general population databases (dbsnp, esp, 1000 genomes),Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation

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